Corneal Neovascularization and Ocular Irritancy Responses in Dogs Following Topical Ocular Administration of an EP4-Prostaglandin E2 Agonist

Prostaglandin receptor agonists have intraocular pressure-lowering effects in humans and are of interest in the treatment of glaucoma. The prostanoid receptor agonist PF-04475270 is a potent and selective agonist of the prostaglandin E-2 receptor EP4. This paper characterizes the toxicity associated with topical Ocular administration of PF-04475270 in beagles. Dogs were given PF-04475270 topically to the eye on a consecutive daily dosing schedule for one or four weeks followed by a one- or four-week reversal period, respectively. Clinical observations, ophthalmic, and laboratory parameters were recorded. Necropsies were conducted at the end of the dosing and recovery phases, and histologic examinations performed. Corneal neovascularization that was considered adverse was observed at doses of >= 1.0 mu g/eye and was not reversed by the end of the recovery phase. Dogs dosed with >= 0.25 mu g/eye developed a dose-related conjunctival hyperemia that persisted throughout the reversal period. Cortical neovascular cells stained positive with EP4 and the endothelial biomarker Factor VIII-vWF. Other histopathology findings observed at doses of >= 1.0 mu g included single-cell necrosis and neutrophils in the cornea, inflammatory cell infiltrates in the iris/ciliary body, and iridal endothelial cell hypertrophy. A resolving acute to subacute inflammation in the iris/ciliary body was observed after the four-week recovery period.